tbuckley/cabot-search huggingface dataset:
BIOM-64. TARGETING IDENTIFICATION OF HOST-BRAIN CANCER SYSTEMIC CYTOKINE SIGNALLING FOR EARLY DETECTION AND TUMOUR SUB-TYPING
Authors: Paul Brennan, Matt Baker
Journal: Neuro-Oncology (2022)

Abstract Background The host-tumour interaction is fundamental to brain tumour biology, orchestration of which is mediated in part by cytokines. We reasoned that detection of a tumour-specific cytokine profile in patient serum could contribute to early diagnosis strategies, and permit prediction of tumour subtypes before histological diagnosis. METHOD Patient serum blood samples (300ul) were collected prospectively from patients with radiological evidence of a new brain tumour diagnosis pre-treatment, and from symptom-matched patients without radiological evidence of a tumour (controls). Our in-house cytokine assay incorporates antibodies captured onto a nitrocellulose slide. 64 capture antibodies are printed per slide, with 4 replicates per antibody. Fluorescence is measured from a biotin secondary antibody, the signal compared to a standard curve, and the averaged relative intensity across 4 replicates determined. We used a hierarchical clustering strategy to examine the relative expression of all 64 biomarkers for each patient class, and for cancer versus non-cancer. We refined this to identify the most discriminatory biomarkers. We made a univariate examination of the association of each antibody with brain tumour type. RESULTS Cytokine profiles were collected from 83 patients (42 glioblastoma, 8 meningioma, 12 metastatic cancer, 6 grade III gliomas, 3 grade II gliomas, 2 other brain tumours, 10 non-cancer patients). The top 4 biomarkers with greatest separation for brain cancer versus non-cancer were osteopontin, MMP3, MMP9 and TIMP-1. A principal component analysis demonstrated clear separation between clusters for these biomarkers. Univariate analysis evidenced discrimination of tumour subtypes, for example MMP9 and oligodendrogliomas. CONCLUSION Cytokine signals can be identified in small volumes of patient serum and used to identify brain cancer ‘risk.’ This could support prioritization for brain imaging, and prediction of tumour subtype to guide pre-operative management decision-making. Combination with other liquid biopsy strategies such as serum spectroscopy may improve spectroscopy test performance and utility.
DNAR-05. A ROLE FOR TAZ/YAP IN DNA DAMAGE REPAIR IN GLIOBLASTOMA
Authors: Krishna Bhat, Krishna Bhat, Tiffany Tang
Journal: Neuro-Oncology (2022)

Abstract Previous studies have shown that glioma stem-like cells (GSCs) evade conventional cytotoxic therapies and repopulate as recurrent tumors. A fuller understanding of the molecular mechanisms underlying the biology and therapy resistance of GSCs is required. Our group has shown that TAZ, a transcriptional co-factor is highly expressed in about 70% of glioblastomas (GBMs). TAZ and its paralog YAP are oncogenic drivers of brain tumor progression. GSCs overexpressing TAZ undergo a proneural (PN) to mesenchymal (MS) subtype transition, which is accompanied by aggressive phenotypes such as increased grade and treatment resistance in GSC xenografts. Although the oncogenic functions of TAZ/YAP are well established, the exact molecular mechanisms underlying TAZ/YAP mediated cell fate transition and therapy resistance in GBM are not fully understood. Here, we present novel functional interaction between TAZ/YAP and DNA-dependent protein kinase (DNA-PK) in response to exposure to ionizing radiation in GSCs. Mass-spectrometric analyses of TAZ-binding proteins showed that DNA-PK complex composed of the catalytic subunit (DNA-PKcs) and a Ku heterodimer of Ku70 and K80 interacted with TAZ. Immunoprecipitation of DNA-PK showed interaction of both YAP as well. Interaction of YAP/TAZ with DNA-PK complex and TEAD was enhanced by ionizing radiation. DNA-PKcs phosphorylated both YAP and TAZ, and phosphorylation level of these proteins were increased after irradiation, consistent with an increased interaction of these proteins. Intriguingly, siRNA knockdown of YAP and TAZ resulted in inactivation of DNA-PKcs, although protein stability of DNA-PKcs was not affected. Pharmacological inhibition of TAZ/YAPTEAD resulted in increased DNA damage and suppressed cell proliferation, and this effect was synergized by irradiation. We conclude that TAZ and YAP are integral components of DNA damage response and that pharmacological targeting of TAZ/YAP/TEAD pathway can overcome radiation resistance in GSCs.
NIMG-41. NON-INVASIVE TRACKING OF T-CELL RECRUITMENT TO THE TUMOR MICROENVIRONMENT IN A MURINE GLIOMA MODEL BY HIGH FIELD CELLULAR MRI
Authors: Jessica Hunger, Katharina Schregel, Manuel Fischer, Dennis Agardy, Volker Sturm, Kianush Karimian-Jazi, Theresa Bunse, Sabine Heiland, Wolfgang Wick, Martin Bendszus, Michael Platten, Michael Breckwoldt
Journal: Neuro-Oncology (2022)

Abstract Gliomas are characterized by increased T cell exhaustion and poor T cell infiltration into the tumor as well as an overall highly immunosuppressive tumor microenvironment (TME). Response rates in preclinical glioma models and patients to promising new therapeutic approaches in the field of immunotherapies - such as checkpoint blockade, vaccines and adoptive therapy with chimeric antigen receptor (CAR) or T cell receptor (TCR)-transgenic T cells - remain heterogeneous. This demonstrates the need for non-invasive tracking of T cell recruitment to the TME in order to monitor T cell activating immunotherapies, adapt therapeutic strategies and predict treatment outcome. Iron oxide nanoparticles (NP) can be visualized non-invasively by magnetic resonance imaging (MRI) and dedicated MRI sequences such as T2* mapping. Using isolated murine T cells cultures we show that labeling of T cells with iron oxide NP as contrast agent is feasible and does not impact T cell viability and functionality as assessed by cytokine secretion and antigen-specific killing activity in vitro. We demonstrate that adoptively transferred T cells can be visualized intratumorally in a murine glioma model by high field MRI at 9.4 Tesla with high sensitivity and that T cells can be tracked non-invasively in a time course of over one week. Ongoing work assesses preclinical efficacy of adoptive T cell therapy targeting well characterized model antigens expressed in experimental gliomas using longitudinal MRI to visualize spatial and temporal T-cell dynamics in the TME. Correlative methods include immunohistochemistry, flow cytometry, tissue clearing and ultramicroscopy. We hypothesize that T cell distribution and numbers may predict therapeutic efficacy and correlate with treatment outcome in experimental gliomas.
NIMG-16. COMPARISON OF A STIR- AND T1-WEIGHTED-BASED RADIOMICS MODEL TO DIFFERENTIATE BETWEEN PLEXIFORM NEUROFIBROMAS AND MALIGNANT PERIPHERAL NERVE SHEATH TUMORS IN NEUROFIBROMATOSIS TYPE 1 (NF1)
Authors: Ina Ly, Tianyu Liu, Wenli Cai, Olivia Michaels, Daniel Kwon, Miriam Bredella, Justin Jordan, Dana Borcherding, Demetrius Boswell, Crystal Burgess, Ping Chi, Peter de Blank, Eva Dombi, Angela Hirbe, Bruce Korf, Shernine Lee, Victor Mautner, Mairim Melecio-Vázquez, Zachary Mulder, Kai Pollard, Christine Pratilas, Johannes Salamon, Divya Srihari, Matthew Steensma, Brigitte Widemann, Jaishri Blakeley, Scott Plotkin
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Plexiform neurofibromas (PNF) and malignant peripheral nerve sheath tumors (MPNST) are best visualized on short TI inversion recovery (STIR) sequences on MRI. However, STIR sequences are not routinely acquired in the clinical setting. T1-weighted pre-contrast (T1W) sequences are more standardly obtained but provide insufficient contrast for tumor identification. We developed a radiomics model based on STIR and T1W sequences to differentiate between NF1-associated PNF and MPNST. METHODS Using a 3D quantitative imaging analysis software (3DQI), 68 MPNST and 79 PNF from 134 participants at nine centers were segmented on STIR sequences (if available) or T2 fat-saturated or T1-weighted fat-saturated post-contrast sequences. Tumor regions of interest were co-registered to T1W sequences. Standard pre-processing included N4 bias field correction, intensity normalization (mean 120 SI, SD 80 SI), and resampling (1 mm3 voxel resolution). 107 radiomic features were extracted using PyRadiomics. To classify tumors as PNF or MPNST, we applied the Boruta algorithm and correlation removal for selection of important features. A Random Forest model was built using the top five selected features. The data were divided into a training/validation and test set (7:3 ratio). Five-fold cross-validation was performed and repeated 100 times. Model performance was evaluated using AUC, sensitivity, specificity, accuracy, and 95% CI. RESULTS For the STIR-based model, AUC was 0.856 (95% CI 0.727-0.984), sensitivity 0.6, specificity 0.833, and accuracy 0.727 in the test set. For the T1W-based model, AUC was 0.867 (95% CI 0.743-0.990), sensitivity 0.8, specificity 0.79, and accuracy 0.794 in the test set. CONCLUSIONS Our radiomics models demonstrate high and comparable performance to distinguish between PNF and MPNST on STIR and T1W sequences. Our inclusion of multicenter MRIs enhances model generalizability. These models can potentially be integrated into the radiologic workflow to help clinicians in the early identification of MPNST or pre-malignant atypical neurofibromas on clinical MRIs.
QOL-22. IDENTIFYING HEALTH STATUS PROFILES AMONG LONG-TERM CNS TUMOR SURVIVORS: A LATENT PROFILE ANALYSIS
Authors: Macy Stockdill, Terri Armstrong, Tito Mendoza, Christine Miaskowski, Bruce Cooper, Elizabeth Vera
Journal: Neuro-Oncology (2022)

Abstract CNS tumors are associated with a high mortality rate, quick onset, limited therapeutic options, and a devastating symptom burden that has a negative impact on general health status and results in functional limitations. While research is focused on development of new therapies, little is known about the health status of long-term survivors. We aimed to identify subgroups of CNS tumor survivors ( &amp;gt; 5 years from diagnosis) with distinct health profiles using latent profile analysis ordinal logit estimation in Mplus V8.8. General health status was measured using the EQ-5D-3L (dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Associations with demographic/clinical characteristics were identified with Pearson’s correlations and chi-square tests. Sample median age was 48 years (range: 21-85), 54% were male, 82% Caucasian, 56% employed, and 53% had a KPS ≥ 90. Most had a high-grade glioma (60%), at least one recurrence (70%), and 17% were on active treatment. Two subgroups were identified: good health status (GHS) (n=183) and poor health status (PHS) (n=115). Most patients in the GHS ( &amp;gt; 86%) reported no issues with mobility or usual activities and 100% had no self-care issues. However, 38% did report some problems with anxiety and depression and 21% had pain. PHS class was characterized by &amp;gt; 94% having at least moderate issues with mobility and usual activities and over 50% having pain, self-care issues, and anxiety and depression. Older age (r=0.21), spine tumors (OR=3.3), active treatment at assessment (OR=2.9), tumor recurrence (OR=4.2), unemployment (OR=3.5), and poor KPS scores (OR=18.1) were associated with belonging in the PHS. While maintaining physical health and function may contribute to better health status in long-term survivors, patients dealing with tumor recurrence, ongoing treatments, and spine tumors may face significant challenges. These functional profiles can be used to develop survivorship care plans and supportive care interventions.
CNSC-24. THE EPILEPTIC LANDSCAPE OF IDH MUTANT GLIOMAS
Authors: Michael Drumm, Wenxia Wang, Kirsten B Burdett, Thomas Sears, Rodrigo Javier, Kristen Cotton, Brynna Webb, Jacob Stolz, Kayla Byrne, Dusten Unruh, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Omar Bushara, Alyssa Weston, Suning He, Rimas Lukas, John Finan, Colin Franz, Jonathan Kurz, Jessica Templer, Geoff Swanson, Craig Horbinski
Journal: Neuro-Oncology (2022)

Abstract Tumor-associated epilepsy (TAE) is a frequent complication of diffusely infiltrative gliomas, and impairs quality-of-life. We previously showed that isocitrate dehydrogenase 1 mutant (IDHmut) gliomas were associated with preoperative seizures, and that D2HG increased synchronized bursts in cultured neurons (PMID: 28404805). But the mechanism whereby this occurs, whether IDHmut inhibitors can block this, and whether seizure risk varies by IDHmut status post-operatively, are unknown. We discovered that exogenous 3 mM D2HG had a 150% greater effect on the firing rate of cultured mouse cortical neurons when nonneoplastic glia cells were present versus when they were absent (P=0.002). Coculture with patient-derived IDHmut glioma cells increased the firing rate of human cortical neuron/astrocyte spheroids by up to 272%, and the IDHmut inhibitor AG881 reduced the excitatory effect of IDHmut glioma cells on spheroids by 79% (P=0.0008). Using a novel in vivo model of TAE, wherein EEG recordings were taken of immunocompetent mice engrafted with isogenic mouse glioma lines (NRAS/ATRX/TP53mut ± IDHmut), we found that IDHmut gliomas produced 7.6-fold more epileptiform spikes than IDHwt gliomas (P=0.004). RNA-Seq analysis of the peritumoral mouse brain tissue showed that this increase in spikes was associated with significantly increased expression of key genes known to be upregulated in epilepsy, including SLC12A5, THSB1, VEGFA, FOSL2, and SYNPO. Treatment with 5 mg/kg AG881 by daily oral gavage reduced those spikes in IDHmut-engrafted mice by 51% within three days (P=0.027), whereas vehicle control had no effect (P=0.33). Among 247 patients with grade 2–4 adult-type diffuse gliomas, multivariable time-to-event analysis showed that post-operative seizure risk was positively associated with pre-operative seizures, subtotal resection, and IDHmut astrocytoma. Together, these data show that (i) the D2HG product of IDHmut gliomas increases neuronal excitation in a glial-dependent manner; (ii) IDHmut also affects post-operative seizure risk; (iii) IDHmut inhibitors may improve TAE control.
EPCO-47. ITCC-P4: GENOMIC PROFILING AND ANALYSES OF PEDIATRIC PATIENT TUMOR AND PATIENT-DERIVED XENOGRAFT (PDX) MODELS FOR HIGH THROUGHPUT IN VIVO TESTING
Authors: Apurva Gopisetty, Aniello Federico, Didier Surdez, Elnaz Saberi-Ansari, Yasmine Iddir, Alexandra Saint-Charles, Joshua Waterfall, Justyna Wierzbinska, Andreas Schlicker, Norman Mack, Benjamin Schwalm, David T Jones, Johannes Gojo, Louis Chesler, Gilles Vassal, Lou Stancato, Jan Koster, Jan J Molenaar, Natalie Jaeger, Gudrun Schleiermacher, Stefan Pfister, Marcel Kool
Journal: Neuro-Oncology (2022)

Abstract Advancements in state-of-the-art molecular profiling techniques has resulted in better understanding of pediatric cancers and their drivers. Conversely, it also became apparent that pediatric cancers are much more heterogeneous than previously thought. Many new types and subtypes of pediatric cancers have been identified with distinct molecular and clinical characteristics. However, for most newly recognized entities there is no specific treatment available yet. The ITCC-P4 consortium is a collaboration between many academic centers across Europe and several pharmaceutical companies involved in preclinical testing, with the overall aim to establish a sustainable platform of &amp;gt;400 molecularly well-characterized PDX models of high-risk pediatric cancers and to use them for in vivo testing of novel mechanism-of-action based treatments. Currently, 340 models are fully established, including 87 brain and 253 non-brain tumor models, together representing different tumor types both from primary (113) and relapsed (92)/metastatic disease (42). 252 of these models have been fully molecularly characterized, representing 18 pediatric cancer entities and 43 different subtypes. Using low coverage whole-genome and whole exome sequencing, somatic mutation calling, DNA copy number, transcriptome analysis and methylation profiling we have observed that the molecular profile of most PDX models closely mimics their original tumors. Clonal evolution of somatic variants was only observed in some PDX-tumor pairs or so between disease states. Somatic copy number variant analysis highlights specific alterations for instance MYB, MYC, MYCN, NTRK3, PTEN loss differently distributed between PDX-patient tumor pairs in high-grade gliomas. Overall, our results show that we have established &amp;gt;250 PDX models of solid pediatric cancers, that well represents the disease spectrum and that is currently being used for in vivo testing of standard of care drugs and targeted small molecules. Treatment responses will be directly linked to molecular data to identify potential biomarkers for prioritization or deprioritization of individual, patient-specific specific drugs.
EXTH-85. TARGETING CLAUDIN 6 WITH CAR T CELL THERAPY FOR ATYPICAL TERATOID/RHABDOID TUMOR
Authors: Peter Madsen, Allison Stern, Crystal Griffin, Petra Oehm, Benjamin Rengstl, Carina Flemming, Adam C Resnick, Philip B Storm, Jessica Foster
Journal: Neuro-Oncology (2022)

Abstract Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive brain tumor that predominantly affects young children and has an average 5-year survival under 50%. Novel, targeted therapies are desperately needed. Claudin 6 (CLDN6) is a tight junction protein present during development and expressed in up to 70% of ATRT specimens but not in normal tissue, making it a promising immunotherapeutic target. CLDN6-targeted chimeric antigen receptor (CAR) T cells in combination with a CAR T cell–amplifying mRNA vaccine have demonstrated antitumor activity against other CLDN6-expressing cancers in pre-clinical and phase I adult trial (NCT04503278; Haanen J et al AACR, 2022). To assess the effectiveness of CLDN6-targeted CAR T cells against ATRT, we utilized a second-generation mRNA CAR with a 4-1BB costimulatory domain and single-chain variable fragment against CLDN6 (Reinhard et al, 2020). Patient-derived ATRT specimens were assessed by RNAseq for CLDN6 expression (mean FPKM= 11.4) and by immunohistochemistry (positive staining in 53% of specimens). Tumor-derived cell lines were validated for CLDN6 expression by flow cytometry. Co-culture of CLDN6-directed mRNA CAR T cells with ATRT cell line 7316-2187 resulted in tumor-specific cytotoxicity compared to CD19-directed control CAR T cells (92% versus 15% at 10:1, p&amp;lt; 0.0001; 86% versus 0% at 5:1, p&amp;lt; 0.0001). Similar results were seen with ATRT cell line 7316-2141 (75% versus 7% at 10:1, p&amp;lt; 0.0001; 53% versus 0% at 5:1, p&amp;lt; 0.0001). Both CLDN6- and CD19-directed CAR T cells showed no cytotoxicity against CLDN6-negative cell line 7316-4149. Patient-derived xenograft models were also created through intracranial injection of multiple ATRT patient cell lines, and ongoing work will evaluate locoregional administration of CLDN6-directed CAR T cells in orthotopic xenograft models to test in vivo efficacy. This work highlights the potential for targeting CLDN6 via CAR T cell therapy in patients with ATRT as a novel therapeutic strategy for these devastating tumors.
CSIG-17. SCD5 PROTECTS GLIOBLASTOMA STEM CELLS FROM DEATH AND DIFFERENTIATION BY MODULATING INTRACELLULAR LIPID COMPOSITION
Authors: Hayk Mnatsakanyan, Caline Pechdimaljian, Roshani Jha, Alessandro Sammarco, Baolong Su, Kevin J Williams, Steven J Bensinger, Christian E Badr
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common malignant brain cancer in adults, enriched in a small subpopulation of glioma stem cells (GSC), which can drive tumor recurrence and therapeutic resistance. Considerable evidence suggests that the endogenous levels of unsaturated fatty acids (FA) are crucial regulators of GSCs survival and self-renewal. Stearoyl-CoA desaturase-1 (SCD-1) is the most abundant desaturase in humans. We have previously shown that SCD1 activity is required for GSCs self-renewal and brain tumor initiation. However, SCD1 orthologous isoform, SCD5, has been poorly characterized and its potential role in GBM has not been previously reported. We have observed that SCD5 is highly enriched in GSC both at the mRNA and protein levels. Genetic downregulation of SCD5 in GSCs led to a remarkable decrease in stem cell markers, impaired cell viability and the ability to form neurospheres. Further, the downregulation of SCD5 in GSCs orthotopically implanted in mice resulted in delayed tumor growth and extended overall survival. Shotgun lipidomics in GSCs after either SCD1 or SCD5 knock-down revealed a largely distinctive lipidome profile, highlighting the divergent role of these two isoforms in GBM lipid metabolism. Surprisingly, lipidomics analysis showed that both SCD1 and SCD5 are required to synthesize a variety of lipid species involved in receptor tyrosine kinase (RTKs) and GPCRs signal transduction, directly linking FA synthesis with the oncogenic signaling. We confirmed these results by immunoblot analysis. Using specific tagging and immunofluorescence analysis, we observed that, despite a spatial overlap in SCD1 and SCD5 expression, SCD5 is uniquely present in some subcellular locations. This suggests that different functions of these isoforms could be related to different subcellular localization. Altogether, our results underscore a novel function of SCD isoforms in GSCs metabolism and highlight SCD5 as a potential therapeutic target for GBM.
SURG-20. PREOPERATIVE QUANTITATION OF UNRESECTABLE TUMOR VOLUME USING WHOLE-BRAIN TRACTOGRAPHY TO IMPROVE OUTCOME PREDICTION AFTER SURGERY FOR HIGH-GRADE DIFFUSE GLIOMAS
Authors: Halle Ronk, William Cheung, Nitish Seenarine, Raymund Yong
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Because minimizing injury to critical brain regions during high-grade glioma (HGG) surgery is essential, the optimal extent of resection (EOR) for any given patient is often less than 100% of the tumor bulk. However, there are no accepted methods of assessing the upper limit of EOR. Advances in whole-brain tractography (WBT) present an opportunity to address this problem. Here, we develop a predictive model for surgical outcomes in HGG as classified by WHO CNS5, and leverage it to determine the added utility of a WBT-based volumetric resectability metric. METHODS We included patients who underwent biopsy or resection of a new or recurrent HGG by the senior author from 2013 to 2020. A volumetric tumor analysis method incorporating WBT was developed to calculate EOR and unresectable tumor volume (UTV). Using perioperative clinical data, multiple linear and Cox regression models were used to identify independent predictors of EOR and progression-free survival (PFS). RESULTS A total of 151 HGGs were included. Median EOR and PFS were 97.0% and 5.0 months, respectively. Greater EOR strongly predicted longer PFS overall (hazard ratio [HR]=0.21, 95% confidence interval [CI] 0.07-0.72), with the largest PFS benefit observed at &amp;gt; 85% EOR. When controlling for EOR, higher residual tumor volume (RTV) predicted longer PFS (HR=0.97, 95% CI 0.94-0.99), suggesting the existence of an RTV threshold below which PFS decreases. Involvement of eloquent regions (p=0.0086) and brainstem (p=0.0006) as categorical variables predicted lower EOR but failed to predict shorter PFS. Calculation of UTV based on actual or imputed WBT data was feasible and reliably predicted EOR. CONCLUSION Existing methods of measuring HGG resectability are poorly reproducible and do not independently predict survival. Preoperative measurement of WBT-based UTV, by substituting for EOR, may simplify and improve HGG outcome prediction, allowing neurosurgeons to better assess the surgical candidacy of individual patients.